Our research seeks to identify the essential roles of specific sodium channels in directing nervous system development. Our studies exploit the experimental advantages of zebrafish for genetic and molecular manipulations, embryological analyses, in vivo live imaging and physiological study. Multigene families (SCNA/scna) encode voltage-gated sodium channel a-subunits in both mammals (Nav1) and zebrafish (nav1). Each sodium channel gene (SCNA/scna) displays a specific expression pattern with respect to space and time. Although several isotypes are expressed during development of the nervous system, little is known about the developmental roles that sodium channels play in the embryonic vertebrate nervous system. Our studies focus on the scn8aa gene, because it is expressed during vertebrate nervous system development. Further, knock-down of its encoded protein, nav1.6a, perturbs development of several neuronal populations in the spinal cord and periphery. In mammals, genetic elimination of the homologous gene (SCN8A) leads to severe neurological deficits as assessed at late postnatal stages. However, the extent to which embryonic events contribute to the phenotypes has not been investigated. The results of the proposed studies are expected to provide important new information about the role(s) of voltage-gated sodium channels in directing key aspects of spinal cord and peripheral sensory neuron development. We propose two specific Aims that will test the roles of nav1.6a in development of motor neurons (Aim 1) and neural crest-derived dorsal root ganglia (Aim 2). Importantly, our preliminary data indicate that nav1.6a acts both cell-autonomously as well as non-cell-autonomously in the embryonic nervous system. Overall, the proposed studies are expected to identify essential roles of nav1.6a in the developing vertebrate nervous system. [unreadable] [unreadable] [unreadable]